Interruption of an organ's blood flow, with its subsequent lack of oxygen and nutrient supply, is only part of ischemia-related tissue injury. Once the blood flow and oxygen supply are reestablished, reperfusion enhances the injury caused by the ischemic period, aggravating the damage caused at the cellular level. This phenomenon, known as ischemia-reperfusion injury, directly impacts tissue viability.
During an ischemic period, several functional changes occur at the cellular level that promote cell injury. A decrease in oxidative phosphorylation results in ATP depletion and derangements in calcium homeostasis. The deleterious effects of ATP depletion are further enhanced by the production of several substances, including reactive oxygen species (ROS), cytokines, adhesion molecules, and vasoactive agents (endothelin and thromboxane-A2). Factors most frequently implicated in ischemia-reperfusion injury are TNF-α, interleukin 1 (IL-1) and interleukin 6 (IL-6), prostaglandins (PG), and ROS, especially superoxide (O2−) and hydrogen peroxide (H2O2). During reperfusion, tumor necrosis factor alpha (TNF-α) and other mediators activate many of the proteins involved in apoptosis, such as the proteases caspase-3 and caspase-8, along with mitochondria cytochrome-C release to the cytoplasm.
These alterations are accompanied by a decrease of cytoprotective substances including nitric oxide (NO) and prostacyclin. NO is synthesized from L-arginine by the action of nitric oxide synthase (NOS). NO is an important mediator of immunomodulation, neurotransmission, and platelet aggregation. Within endothelial cells, NO triggers cGMP to reduce vascular tone and act as a vasodilator. NO can mediate the intensity of the ischemia-reperfusion injury by modulating neutrophil adhesion, platelet aggregation, and vasoconstriction. The balance between vasorelaxation and vasoconstriction is affected by the balance between endothelin (ET) and NO. Therefore, one of the mechanisms involved in ischemia-reperfusion injury is loss of the equilibrium between ET and NO levels during reperfusion. At the beginning of reperfusion, NO levels decrease and ET levels increase, favoring microcirculatory vasoconstriction.
Ischemia ultimately leads to cell death if not resolved by reperfusion. Studies by Reimer and Jennings and colleagues laid the foundation for early reperfusion as the definitive approach to treat acute myocardial infarction. Reimer et al. (1977) Circulation 56:786-794. The study by DeWood et al. (1980)N. Engl. J. Med. 303:897-902, demonstrating that acute myocardial infarction was largely an occlusive event of sudden onset, due to thrombus formation in the affected coronary artery, set the stage for thrombolysis as an approach to restore reflow to the infarct-related artery. Infarct size reduction is an important therapeutic goal since it is linked to other short- and long-term outcomes such as arrhythmias, mortality, and loss of productivity. In addition, the size of the infarct is related to the incidence and severity of heart failure. Therefore, it is important to salvage as much myocardium as possible, historically by initiating reperfusion as rapidly as possible.
While the majority of therapeutic approaches for treatment of acute evolving myocardial infarction have been designed to reduce the duration and severity of ischemia; newer generation approaches target reperfusion injury. Various approaches have been taken to attenuate reperfusion injury, including the systemic or local infusion of adenosine, nitric oxide, oxygen radical scavengers, anti-inflammatory agents, and the filtration of inflammatory cells at the time of reperfusion.